The overt symptoms and deficits of schizophrenia (SZ) typically begin to emerge during late adolescence and early adulthood, followed by a period of post-onset functional deterioration. This peri-onset period temporally coincides with the final maturation of the prefrontal cortex (PFC), which is characterized by a process of extensive pruning of synaptic connectivities. Increasing evidence suggests that upregulation of GABA neurotransmission, especially one that is mediated by the fast-spiking GABA cells that contain the calcium-binding protein parvalbumin (PV), which include the perisomatically targeting basket cells and the axo-axonic projecting chandelier cells, may play an important role in regulating the timing of the completion of peri-adolescent synaptic pruning. Interestingly, deficient PV neuronal functions and deficits of synaptic connectivities are increasingly recognized as key pathophysiologic features of SZ. Thus, there may be at least 2 mechanisms that may mediate the onset and early progression of SZ by contributing to PFC synaptic deficits: (1) Deficient GABA neurotransmission may prolong synaptic pruning, leading to excessive loss of synapses and (2) Reduced GABA inhibition may disinhibit pyramidal cells, making them prone to excitotoxic injury, which can be manifested as dendritic shrinkage and synaptic attrition. Thus, enhancement of GABA neurotransmission during the early course of SZ may, in the first scenario, normalize aberrant synaptic pruning and, in the second scenario, attenuate excitotoxicity-induced synaptic loss. In other words, GABA enhancement may restore the integrity of PFC neural circuits, which may then lead to lasting improvement in cognitive deficits and clinical symptoms. The proposed study will test this concept, focusing especially on working memory (WM), a key cognitive function mediated by the PFC. Thirty-six SZ subjects with onset of psychosis within 3 years, male or female, between 18-25 years of age, will be randomized to receive tiagabine (Gabitril), a selective inhibitor of the GABA transporter GAT-1, which may preferentially enhance GABA neurotransmission furnished by the PV-containing GABA cells during the peri-onset period, or placebo, added onto their regimen of second-generation antipsychotics, excluding clozapine. We will use a 2-back WM task and the WM sub-tests of the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) battery to assess possible improvement in WM. In addition, we will explore whether tiagabine may also improve positive and negative symptoms, as evaluated by clinical rating scales, and other aspects of cognition, including attention, processing speed, reasoning, and social cognition, as measured by tests in the MATRICS battery. This proof-of-concept study was conceptualized based on rather compelling preclinical data and may offer a completely new dimension in our thinking about the early intervention and prevention of SZ. PUBLIC HEALTH RELEVANCE The goal of this study is to test the hypothesis that enhancement of inhibitory neural transmission during the early course of schizophrenia may improve cognitive and symptomatic deficits.